"Siglec"ting the allergic response for therapeutic targeting

Abstract

As a physician-scientist, I have pursued research related to translational immunology with the goal of improving our ability to diagnose and treat allergic, immunologic and other diseases involving eosinophils, basophils and mast cells. We have tried to delineate novel mechanisms of human disease, working whenever possible with primary human cells and tissues, attempting to identify targets that might be amenable to the development of new therapies. As a general strategy, we have compared eosinophils, basophils, mast cells and neutrophils to look for pathways in inflammation that were unique to distinct subsets of these cells. In doing so, the concepts of glycobiology did not enter my mind until we began noticing some intriguing functional differences involving selectins and their ligands among these cell types. One simple observation, that neutrophils were coated with a glycan that allowed them to interact with an endothelial adhesion molecule while eosinophils lacked this structure, pried open the glyco-door for me. Fruitful collaborations with card-carrying glycobiologists soon followed that have forever positively influenced our science, and have enhanced our hypotheses, experimental design, research opportunities and discoveries. Within a few years, we helped to discover Siglec-8, an I-type lectin expressed only on human eosinophils, basophils, mast cells. This receptor, together with its closest mouse counterpart Siglec-F, has been the primary focus of our work now for over a decade. If not for those in the fields of glycobiology and glycoimmunology, my lab would not have made much progress toward the goal of leveraging Siglec-8 for therapeutic purposes.

Keywords: eosinophil; glycans; mast cell; sialic acid; siglecs.

Fig. 1.

Expression of SAF-2 (Siglec-8, as detected by monoclonal antibody 2C4) on human peripheral blood eosinophils, basophils and 16-week-old cord blood-derived cultured mast cells. Histograms shown are representative of 3–4 experiments with virtually identical results for each cell type. Monoclonal reagents used as positive and negative controls are also shown. Reproduced from Kikly et al. (2000) with permission.

Fig. 2.

Results from the Siglec-8-Ig glycan binding array analysis. A total of 172 glycans were screened for binding along with positive and negative controls, as described under Experimental procedures. Error bars represent mean ± SD replicate determinations from a single experiment. Note that ligand 181 (6′-sulfo-sLex) stands out among all the others for binding activity. RFU, relative fluorescence units. Reproduced from Bochner et al. (2005) with permission.

Fig. 3.

Too many eosinophils in the airway can worsen asthma (A). Murine studies by Kiwamoto et al. (2015) found that specific sialoglycans on the mucus protein Muc5b, normally found in the airway, engage Siglec-F and cause eosinophil death (B). This represents a potential pathway by which endogenous airway mucins, via specific glycosylation patterns, can influence innate immune responses. Illustration by Jacqueline Schaffer.